N-
acetyl-seryl-aspartyl-lysyl-proline (
AcSDKP) is an endogenous antifibrotic
peptide. We found that suppression of
AcSDKP and induction of dipeptidyl peptidase-4 (DPP-4), which is associated with insufficient levels of antifibrotic
microRNA (miR)s in kidneys, were imperative to understand the mechanisms of
fibrosis in the diabetic kidneys. Analyzing
streptozotocin (STZ)-induced diabetic mouse strains, diabetic CD-1 mice with fibrotic kidneys could be differentiated from less-fibrotic diabetic 129Sv mice by suppressing
AcSDKP and antifibrotic miRs (miR-29s and miR-let-7s), as well as by the prominent induction of DPP-4
protein expression/activity and endothelial to mesenchymal transition. In diabetic CD-1 mice, these alterations were all reversed by
AcSDKP treatment. Transfection studies in culture endothelial cells demonstrated crosstalk regulation of miR-29s and miR-let-7s against mesenchymal activation program; such bidirectional regulation could play an essential role in maintaining the antifibrotic program of
AcSDKP. Finally, we observed that
AcSDKP suppression in fibrotic mice was associated with induction of both
interferon-γ and
transforming growth factor-β signaling, crucial molecular pathways that disrupt antifibrotic miRs crosstalk. The present study provides insight into the physiologically relevant antifibrotic actions of
AcSDKP via antifibrotic miRs; restoring such antifibrotic programs could demonstrate potential utility in combating kidney
fibrosis in diabetes.